Mild myopathy is associated with COMP but not MATN3 mutations in mouse models of genetic skeletal diseases.

Piróg KA, Katakura Y, Mironov A, Briggs MD - PLoS ONE (2013)

Bottom Line:
Interestingly, recent reports suggest patients can also manifest with muscle weakness.T3-COMP tendons became more lax in cyclic testing and showed thicker collagen fibers when compared with wild-type tissue; matrilin-3 mutant tissues were indistinguishable from controls.This comprehensive study of the myopathy associated with PSACH/MED mutations enables a better understanding of the disease progression, confirms that it is genotype specific and that the limb weakness originates from muscle and tendon pathology rather than short-limbed dwarfism itself.

ABSTRACTPseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are skeletal disorders resulting from mutations in COMP, matrilin-3 or collagen IX and are characterised by short-limbed dwarfism and premature osteoarthritis. Interestingly, recent reports suggest patients can also manifest with muscle weakness. Here we present a detailed analysis of two mouse models of the PSACH/MED disease spectrum; ΔD469 T3-COMP (PSACH) and V194D matrilin-3 (MED). In grip test experiments T3-COMP mice were weaker than wild-type littermates, whereas V194D mice behaved as controls, confirming that short-limbed dwarfism alone does not contribute to PSACH/MED-related muscle weakness. Muscles from T3-COMP mice showed an increase in centronuclear fibers at the myotendinous junction. T3-COMP tendons became more lax in cyclic testing and showed thicker collagen fibers when compared with wild-type tissue; matrilin-3 mutant tissues were indistinguishable from controls. This comprehensive study of the myopathy associated with PSACH/MED mutations enables a better understanding of the disease progression, confirms that it is genotype specific and that the limb weakness originates from muscle and tendon pathology rather than short-limbed dwarfism itself. Since some patients are primarily diagnosed with neuromuscular symptoms, this study will facilitate better awareness of the differential diagnoses that might be associated with the PSACH/MED spectrum and subsequent care of PSACH/MED patients.

Mentions:
Finally, there were more fused/branching collagen fibers (Figure 4C inset) present in T3-COMP mutant Achilles tendons at 3 weeks of age (Figure 4C; ~2-fold p<0.05) and we have previously shown a similar difference for the CTD-COMP mutation (Figure 4C; ~4-fold p<0.05[25]). The trend towards the greater number of bifurcating fibers in the CTD-COMP mutant may be a means for compensating for thinner and therefore more lax tendons. In contrast, mutant matrilin-3 and wild type tendons were the same thickness at 3 weeks of age (Figure 5A) and showed a normal bell curve distribution of collagen fiber diameters (Figure 5B, no statistically significant differences). Furthermore, there was no increase in the number of branching/fused collagen fibers between the wild type and mutant matrilin-3 tendons (Figure 5C).

Mentions:
Finally, there were more fused/branching collagen fibers (Figure 4C inset) present in T3-COMP mutant Achilles tendons at 3 weeks of age (Figure 4C; ~2-fold p<0.05) and we have previously shown a similar difference for the CTD-COMP mutation (Figure 4C; ~4-fold p<0.05[25]). The trend towards the greater number of bifurcating fibers in the CTD-COMP mutant may be a means for compensating for thinner and therefore more lax tendons. In contrast, mutant matrilin-3 and wild type tendons were the same thickness at 3 weeks of age (Figure 5A) and showed a normal bell curve distribution of collagen fiber diameters (Figure 5B, no statistically significant differences). Furthermore, there was no increase in the number of branching/fused collagen fibers between the wild type and mutant matrilin-3 tendons (Figure 5C).

Bottom Line:
Interestingly, recent reports suggest patients can also manifest with muscle weakness.T3-COMP tendons became more lax in cyclic testing and showed thicker collagen fibers when compared with wild-type tissue; matrilin-3 mutant tissues were indistinguishable from controls.This comprehensive study of the myopathy associated with PSACH/MED mutations enables a better understanding of the disease progression, confirms that it is genotype specific and that the limb weakness originates from muscle and tendon pathology rather than short-limbed dwarfism itself.

ABSTRACTPseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are skeletal disorders resulting from mutations in COMP, matrilin-3 or collagen IX and are characterised by short-limbed dwarfism and premature osteoarthritis. Interestingly, recent reports suggest patients can also manifest with muscle weakness. Here we present a detailed analysis of two mouse models of the PSACH/MED disease spectrum; ΔD469 T3-COMP (PSACH) and V194D matrilin-3 (MED). In grip test experiments T3-COMP mice were weaker than wild-type littermates, whereas V194D mice behaved as controls, confirming that short-limbed dwarfism alone does not contribute to PSACH/MED-related muscle weakness. Muscles from T3-COMP mice showed an increase in centronuclear fibers at the myotendinous junction. T3-COMP tendons became more lax in cyclic testing and showed thicker collagen fibers when compared with wild-type tissue; matrilin-3 mutant tissues were indistinguishable from controls. This comprehensive study of the myopathy associated with PSACH/MED mutations enables a better understanding of the disease progression, confirms that it is genotype specific and that the limb weakness originates from muscle and tendon pathology rather than short-limbed dwarfism itself. Since some patients are primarily diagnosed with neuromuscular symptoms, this study will facilitate better awareness of the differential diagnoses that might be associated with the PSACH/MED spectrum and subsequent care of PSACH/MED patients.